Smooth muscle tone and exocrine gland secretion in several organ systems are modulated by the autonomic nervous system. Whereas cholinergic nerves releasing acetylcholine increase both airway smooth muscle tone and intraluminal secretion of water and electrolytes, recent in vitro and in vivo studies have shown that airway smooth muscle tone is decreased by two additional distinct autonomic neural mechanisms. Adrenergic nerves releasing norepinephrine appear to relax smooth muscle through a beta-adrenergic receptor mechanism while nonadrenergic noncholinergic (NANC) nerves releasing an as yet undetermined neurotransmittor relax smooth muscle through an undefined mechanism. Studies on the modulation of airway secretions by adrenergic and NANC nerves have not been reported. Using electrical nerve stimulation techniques and an in situ innervated guinea pig tracheal preparation I recently demonstrated in vivo the presence of airway NANC nerves. I also described the vagus nerve/recurrent laryngeal nerve anatomic pathway of NANC nerves supplying the trachea. In this research plan employing the same guinea pig experimental model which allows separation and comparison of responses of intrathoracic and extrathoracic airways we propose to study the role in vivo of the NANC nerves of the airways using physiological, neurophysiological, pharmacological, and biochemical techniques. After pharmacological eliminating cholinergic and adrenergic nerve effects we will determine: 1) whether NANC nerves attenuate airway contraction response to broncho-constrictor stimuli such as intravenous histamine, serotonin, prostaglandin F2alpha, and alpha-adrenergic receptor agonists in addition to bronchoconstriction induced by arterial hypoxemia; 2) whether NANC nerve induced decreases in smooth muscle tone are responsible for the reflex bronchodilation observed during sustained high line inflation; and 3) whether electrical stimulation of NANC nerves, adrenergic nerves, or cholinergic nerves modulate transtracheal fluxes of water and electrolytes.